1. Field of the Invention
The present invention relates to quinuclidine esters of 1-azaheterocyclylacetic acid analogues which act as muscarinic receptor antagonists. The present invention also relates to processes for the preparation of such quinuclidine esters of 1-azaheterocyclylacetic acid analogues, compositions which comprise such quinuclidine esters of 1-azaheterocyclylacetic acid analogues, and therapeutic uses of such quinuclidine esters of 1-azaheterocyclylacetic acid analogues.
2. Discussion of the Background
Quaternary ammonium salts which act as muscarinic (M) receptor antagonist drugs are currently used in therapy to induce bronchodilation for the treatment of respiratory diseases. Examples of well known M receptor antagonists are represented by ipratropium bromide and tiotropium bromide.
Several chemical classes which act as selective muscarinic M3 receptor antagonist drugs have been developed for the treatment of inflammatory or obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Quinuclidine carbamate derivatives and their use as M3 antagonists are for instance disclosed in WO 02/051841, WO 03/053966, and WO 2008/012290, all of which are incorporated herein by reference in their entireties.
WO 2010/015324, which is incorporated herein by reference in its entirety, describes carbonate derivatives and their use as M3 antagonists.
1-ethyl-3-piperidinyl ester of optionally substituted alfa-phenyl-1-piperidine-/1-pyrrolidine-/4-morpholine-acetic acid have been described for their spasmolytic activity with respect to acetylcholine in U.S. Pat. No. 2,952,685 and in Bull. Soc. Chim. France, 355-359, 1958, which are incorporated herein by reference in their entireties.
1-methyl-3-piperidinyl ester of alfa-phenyl-1-piperidine-acetic acid and analogues have been prepared and tested as potential psychotropic drugs for their psychotomimetic properties in Chim. Ther., 7, 408-414, 1966, which is incorporated herein by reference in its entirety.
Quaternary ammonium salts of quinuclidine esters of alfa-phenyl-alfa-methyl-1-piperidine-acetic acid and analogues have been described in WO 2008/075005, WO 2009/153536, and Bioorg Med Chem Lett (2011), doi:10.1016/j.bmcl.2011.10.002, which are incorporated herein by reference in their entireties. Said compounds which have a methyl group in place of the hydroxyl group of the well known M3 antagonists of the prior art (tiotropium, glycopyrrolate, aclidinium bromide) would have higher probability to bind to plasma proteins.
It is however highly desirable to provide M3 receptor antagonists which can be administered by inhalation, are capable of acting locally, while having a high potency and long duration of action. Said drugs, once adsorbed, should be degraded to inactive compounds which are deprived of any systemic side effects typical of muscarinic antagonists.